The present invention relates to the field of cancer treatment and is based on the discovery that betulinic acid and its derivatives are potent anti-neuroectodermal agents. As disclosed herein, betulinic acid and its derivatives are useful for the treatment of neurodectodermal tumors, due to its distinct mechanism of action, including neuroectodermal tumors that are resistant to conventional chemotherapeutical agents. In addition to the new use of known compounds, the invention discloses novel compounds and pharmaceutical compositions for the treatment of neuroectodermal tumors.
Neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing""s sarcoma, representing the most common solid tumors of childhood. Chemotherapy is the primary treatment for many types of neuroectodermal tumors. Two thirds of the neuroblastoma cases occur in children of 5 years of age or younger. The early onset of neuroblastoma is illustrated by prenatal neuroblastoma detectable by fetal ultrasonography. Jennings et al 1993, J. Ped. Surg. 28:1168-1174. Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. Neuroblastoma presents serious clinical consequences including symptoms associated with tumor mass or bone pain from metastases. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord, causing paralysis. Azizkhan and Haase, 1993, Sem. Surg. Oncol. 9: 493-501. Approximately 70% of all patients with neuroblastoma have metastatic disease at diagnosis. See, e.g., Brodeur et al., 1993, J. Clin. Oncol. 11: 1466-1477; Adams et al., 1993, J. Ped. Surg. 28:372-378; Evans et al., 1976, Cancer 38:661-666.
Chemotherapy remains to be one of the most effective treatments for neuroblastoma tumors. Neuroblastoma patients are generally treated with chemotherapy with cyclophosphamide and doxorubicin, cisplatin with teniposide or etoposide or vincristine with cisplatin and teniposide or etoposide for more resistant tumors. For patients younger than one year, aggressive chemotherapy using combinations of cyclophosphamide, doxorubicin, cisplatin, and teniposide or etoposide is generally used. Castleberry et al., 1991, J. Clin. Oncol. 9:789-795; Bowman et al., 1997, J. Natl. Cancer Inst. 89:373-380; Castleberry et al., 1992, J. Clin. Oncol. 10:1299-1304.
Aggressive multiagent chemotherapy has resulted in a 2-year survival rate of approximately 20% in older children with stage IV neuroblastoma. Bowman et al., 1991, J. Clin. Oncol. 9:1599-1608; Williams et al., 1995, Med. Ped. Oncol. 24:176-180. Neuroblastoma in the adolescent or adult has a worse long-term prognosis regardless of stage or site and, in many cases, a more prolonged course. Franks et al., 1997, Cancer 79: 2028-2035.
Ewing""s sarcoma (EWS) usually occurs in bone and is diagnosed most frequently in the second decade of life. The most common sites for the primary lesion are the pelvic bones, femur, humerus, and ribs. Ewing""s sarcoma occurs less commonly at non-bone primary sites, a presentation that has historically been termed extraosseous Ewing""s sarcoma. However, the morphological and biological characteristics of Ewing""s tumors developing in soft tissues appear to be indistinguishable from those of tumors developing at bone sites. Delattre et al., 1994, New Engl. J. Med. 331:294-299; Llombart-Bosch et al., 1990, Cancer 66:2589-2601.
Primitive neuroectodermal tumors (PNETs) have been referred to by different terms depending on their location and extent of neural differentiation: peripheral neuroepithelioma, Askin tumor, adult neuroblastoma, peripheral neuroblastoma, and primitive neuroectodermal tumors. The collective term is primitive neuroectodermal tumors. Ewing""s sarcoma and PNET represent a biological spectrum of the same tumor. Greater than 90% of these tumors are characterized by chromosome 11/22 translocation. Since these tumors exhibit only neuroectodermal markers of differentiation, it has been suggested that they arise from neural crest cells. Because treatment is the same for these tumors, they are often referred to as Ewing""s sarcoma.
Studies suggest that more than 50% of patients without metastatic disease may have a long-term disease-free survival, compared to only 20-30% for patients who present with metastatic disease. See, e.g., Burgert et al., 1990, J. Clin. Oncol. 8:1514-1524; Grier et al., 1994, Proc. Am. Soc. Clin. Oncol. 13: A-1443; Rosen et al., 1981, Cancer 47:2204-2213; Dunst et al., 1995, Int. J. Rad. Oncol. Biol. Phy. 32:919-930; Arai et al., 1991, Int. J. Rad. Oncol. Biol. Phy. 21:1501-1508.
Surgery of Ewing""s sarcoma is usually limited to the initial diagnostic biopsy of the primary tumor. Patients usually underwent induction chemotherapy followed by radiation therapy for local control. The successful treatment of patients with Ewing""s sarcoma requires the use of multidrug chemotherapy. Combination chemotherapy for Ewing""s sarcoma has traditionally included vincristine, doxorubicin, cyclophosphamide, and dactinomycin (VAdriaC or VAC). The importance of doxorubicin has been demonstrated in randomized comparative trials with increased doxorubicin dose intensity during the early months of therapy resulting in improved event-free survival. See, e.g., Nesbit et al., 1990, J. Clin. Oncol. 8:1664-1674; Kinsella et al., 1991, Int. J. Radiat. Oncol. Biol. Phy. 20:389-395; Smith et al., 1991, J. Natl. Cancer Inst. 83:1460-1470.
Although many neuroectodermal tumors initially respond to chemotherapy, the prognosis of children who relapse or present with disseminated disease remain poor, because of the development of drug resistance. Some chemotherapeutical agents, such as doxorubicin, rely upon the presence of functioning CD95 system in the target tumor cells to exert their anti-tumor activities. Cells lacking functional CD95 are resistant to doxorubicin. Some other chemotherapeutical agents relay upon the presence of a functional p53 system to exert their anti-tumor activities. Such chemotherapeutical agents are ineffective against cells lacking functional p53 protein.
Therefore, there is a great need to develop chemotherapeutical drugs that target neuroectodermal tumors and particularly drug resistant neuroectodermal tumors. Accordingly, this invention provides chemical compositions and the use thereof for the treatment of neuroectodermal tumors. Those compositions do not relay upon the CD95 or p53 systems to exert their anti-tumor activities.
The present invention provides novel compounds, useful for treatment of neuroectodermal tumors, having the general formula (I): 
wherein
R1 is selected from the group consisting of hydrogen, xe2x80x94SO3H, xe2x80x94PO3H2, xe2x80x94C1-C20 straight or branched chain alkenyl, xe2x80x94C2-C20 straight or branched chain alkenyl, xe2x80x94C2-C20 straight or branched chain alkynyl, xe2x80x94(CH2CH2O)nH, xe2x80x94(CH2CH2O)nCH3, xe2x80x94(CH2CH2O)nCH2CH3, xe2x80x94C(O)C6H5, xe2x80x94C(O)C1-C20 straight or branched chain alkyl, xe2x80x94C(O)C2-C20 straight or branched chain alkenyl, xe2x80x94C(O)C2-C20 straight or branched chain alkynyl, myo-inosityl, scyllo-inosityl, a cyclitol, conduritol A, quebrachitol, a monosaccharide, a disaccharide and an oligosaccharide; the xe2x80x94(CH2CH2O)nH, myo-inosityl, scyllo-inosityl, cyclitol, conduritol A, quebrachitol, monosaccharide, disaccharide and oligosaccharide being optionally substituted with one or more xe2x80x94C(O)C1-C20 straight or branched chain alkyl, xe2x80x94C(O)C2-C20 straight or branched chain alkenyl, xe2x80x94C(O)C2-C20 straight or branched chain alkynyl, sulfate, or mono-, di- or tri-phosphate groups;
R2 is selected from the group consisting of xe2x80x94CO2H, xe2x80x94CO2(C6H5), xe2x80x94CO2(C1-C20 straight or branched chain alkyl), xe2x80x94CO2(C2-C20 straight or branched chain alkenyl), xe2x80x94CO2(C2-C20 straight or branched chain alkynyl), xe2x80x94CO2(myo-inosityl), xe2x80x94CO2(scyllo-inosityl), xe2x80x94CO2(cyclitol), xe2x80x94CO2(conduritol A), xe2x80x94CO2(quebrachitol), xe2x80x94CO2(monosaccharide), xe2x80x94CO2(disaccharide), xe2x80x94CO2(oligosaccharide), xe2x80x94CO(OCH2CH2)nOH, xe2x80x94CO(OCH2CH2)nOCH3, xe2x80x94CO(OCH2CH2)nOCH2CH3, xe2x80x94CH2OH, xe2x80x94CH2OSO3H, xe2x80x94CH2OPO3H2, xe2x80x94CH2O(C6H5), xe2x80x94CH2O(C1-C2 straight or branched chain alkyl), xe2x80x94CH2O(C2-C20 straight or branched chain alkenyl), xe2x80x94CH2O(C2-C20 straight or branched chain alkynyl), xe2x80x94CH2O2C(C1-C20 straight or branched chain alkyl), xe2x80x94CH2O2C(C2-C20 straight or branched chain alkenyl), xe2x80x94CH2O2C(C2-C20 straight or branched chain alkynyl), xe2x80x94CH2O(myo-inosityl), xe2x80x94CH2O(scyllo-inosityl), xe2x80x94CH2O(cyclitol), xe2x80x94CH2O(conduritol A), xe2x80x94CH2O(quebrachitol), xe2x80x94CH2O(monosaccharide), xe2x80x94CH2O(disaccharide), xe2x80x94CH2O(oligosaccharide), xe2x80x94CH2(OCH2CH2)nOH, xe2x80x94CH2(OCH2CH2)nOCH3, xe2x80x94CH2(OCH2CH2)nOCH2CH3, xe2x80x94CH2O2C(OCH2CH2)nOH, xe2x80x94CH2O2C(OCH2CH2)nOCH3, and xe2x80x94CH2O2C(OCH2CH2)nOCH2CH3; the myo-inosityl, scyllo-inosityl, cyclitol, conduritol A, quebrachitol, monosaccharide, disaccharide, oligosaccharide, xe2x80x94CH2(OCH2CH2)nOH and xe2x80x94CH2O2C(OCH2CH2)nOH being optionally substituted with one or more xe2x80x94C(O)C1-C20 straight or branched chain alkyl, xe2x80x94C(O)C2-C20 straight or branched chain alkenyl, xe2x80x94C(O)C2-C20 straight or branched chain alkynyl, sulfate, or mono-, di- or tri-phosphate groups;
R3 is selected from the group consisting of xe2x80x94C(CH3)(xe2x95x90CH2) and xe2x80x94CH(CH3)2;
each n is independently an integer from 1 to 20;
D-enantiomers, L-enantiomers, and racemates thereof;
and pharmaceutically acceptable salts thereof;
with the proviso that the compound of formula I is not:
3xcex2-3-hydroxylup-20(29)-en-28-oic acid (xe2x80x9cbetulinic acidxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol (xe2x80x9cbetulinxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol diacetate (xe2x80x9c3,28-diacetylbetulinxe2x80x9d);
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-acetylbetulinic acidxe2x80x9d);
3xcex2-3-(1-oxobutoxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-butyrylbetulinic acidxe2x80x9d);
3xcex2-3-(2,3-dihydroxycinnamoyl)lup-20(29)-en-28-oic acid (xe2x80x9c3-(2,3-dihydroxycinnamoyl)betulinic acidxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol 3-acetate (xe2x80x9c3-acetylbetulinxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol 28-acetate (xe2x80x9c28-acetylbetulinxe2x80x9d);
3xcex2-3-hydroxylup-20(29)-en-28-oic acid methyl ester (xe2x80x9cmethyl betulinatexe2x80x9d);
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid methyl ester (xe2x80x9cmethyl 3-acetylbetulinatexe2x80x9d);
3xcex2-3-hydroxylup-20(29)-en-28-oic acid ethyl ester (xe2x80x9cethyl betulinatexe2x80x9d);
3xcex2-3-hydroxylup-20(29)-en-28-oic acid butyl ester (xe2x80x9cbutyl betulinatexe2x80x9d);
3xcex2-lupane-3,28-diol (xe2x80x9cdihydrobetulinxe2x80x9d);
3xcex2-3-hydroxylupan-28-oic acid (xe2x80x9cdihydrobetulinic acidxe2x80x9d);
3xcex2-3-hydroxylupan-28-oic acid methyl ester (xe2x80x9cmethyl dihydrobetulinatexe2x80x9d);
3xcex2-3-(acetyloxy)lupan-28-oic acid methyl ester (xe2x80x9cmethyl 3-acetyldihydrobetulinatexe2x80x9d);
3xcex2-3-(acetyloxy)-lupan-28-oic acid (xe2x80x9c3-acetyldihydrobetulinic acidxe2x80x9d);
3xcex2-lupane-3,28-diol diacetate (xe2x80x9c3,28-diacetyldihydrobetulinxe2x80x9d);
3xcex2-lupane-3,28-diol dibutanoate (xe2x80x9c3,28-dibutyryldihydrobetulinxe2x80x9d);
3xcex2-3-(3-methyl-1-oxobutoxy)lupan-28-oic acid (xe2x80x9c3-(3-methylbutryryl)dihydrobetulinic acidxe2x80x9d);
3xcex2-3-((1-oxo-2-butenyl)oxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-(trans-2-butenyl)betulinic acidxe2x80x9d);
3xcex2-3-(2,2-dimethyl-1-oxopropoxy)lupan-28-oic acid (xe2x80x9c3-(2,2-dimethylpropionyl)dihydrobetulinic acidxe2x80x9d);
3xcex1-28-hydroxylup-20(29)-en-3-yl-6-O-(6-deoxy-xcex1-L-mannopyranosyl)-xcex2-D- glucopyranoside;
3xcex1-28-hydroxylup-20(29)-en-3-yl-xcex2-D-glucopyranoside;
3xcex1,4xcex1-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid;
3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid;
3xcex2-28-hydroxylup-20(29)-en-3-yl-xcex2-D-glucopyranoside;
3xcex2-3-hydroxylup-20(29)-en-28-yl-xcex2-D-glucopyranoside;
3xcex2-28(acetyloxy)lup-20(29)-en-3-yl-2-deoxy-xcex1-D-arabinohexopyranoside triacetate;
3xcex2-28(acetyloxy)lup-20(29)-en-3-yl-2-deoxy-xcex2-L-arabinohexopyranoside triacetate;
3xcex2-28(acetyloxy)lup-20(29)-en-3-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside diacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-2-deoxy-xcex1-D-arabinohexopyranoside triacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside diacetate;
3xcex2-28-hydroxylup-20(29)-en-3-yl-2-deoxy-xcex2-D-arabinohexopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-2-deoxy-xcex2-L-arabinohexopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside;
3xcex2-3-hydroxylup-20(29)-en-28-yl-2-deoxy-xcex1-D-arabinohexopyranoside;
3xcex2-lup-20(29)-en-3,28-diyl-bis-xcex2-D-glucopyranoside;
3xcex2-lup-20(29)-en-3,28-diyl-bis-4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-lup-20(29)-en-3,28-diyl-bis-(4-O-(2,3,4,6-tetra-O-acetyl-xcex1-D-glucopyranosyl)-xcex2-D-glucopyranoside hexaacetate;
3xcex2-3-((4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((6-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-hydroxylup-20(29)-en-28-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside;
3xcex2-3-((2-O-xcex1-L-arabinopyranosyl-6-deoxy-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((2-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid xcex2-D-galactopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid 4-O-xcex2-D-galactopyranosyl-xcex2-D- glucopyranosyl ester;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid methyl ester;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lupan-28-oic acid methyl ester;
3xcex2-3-(acetyloxy)lupan-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex1-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-(acetyloxy)lupan-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid xcex2-D-xylopyranosyl ester;
3xcex2-hydroxylup-20(29)-en-28-oic acid xcex2-D-glucopyranosyl ester 2xe2x80x2,3xe2x80x2,4xe2x80x2,6xe2x80x2-tetrabenzoate;
3xcex2-lup-20(29)-en-28-oic acid (xcex2-D-glucopyranosyloxy)-xcex2-D-glucopyranosyl ester octabenzoate;
3xcex2-lup-20(29)-en-28-oic acid (xcex1-L-arabinopyranosyloxy)-xcex1-L-arabinopyranosyl ester;
3xcex2-lup-20(29)-en-28-oic acid (xcex1-L-arabinopyranosyloxy)-xcex1-L-arabinopyranosyl ester hexabenzoate;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid methyl ester;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lupan-28-oic acid methyl ester;
3xcex2-3-hydroxylupan-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-3-O-xcex2-D-xylopyranosyl-xcex2-D-glucopyranosiduronic acid;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-2-O-xcex2-D-xylopyranosyl-xcex2-D-glucopyranosiduronic acid;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid 6-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranosyl ester;
3xcex1-3-hydroxylup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex1-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex2-28-methoxy-28-oxolup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid methyl ester diacetate;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-xcex2-D-xylopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid diacetate;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)O-3,4-di-O-acetyl-xcex2-D-xylopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid diacetate;
3xcex2-28-methoxy-28-oxolup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid methyl ester diacetate;
3xcex2-28-methoxy-28-oxolup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4-di-O-acetyl-xcex2-D-xylopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid methyl ester diacetate;
3xcex2-3-((O-xcex1-L-arabinofuranosyl-(1xe2x86x922)-O-6-deoxy-xcex1-L-matnopyranosyl-(1xe2x86x924)-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((O-xcex1-L-arabinofuranosyl-(1xe2x86x922)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-xcex2-D-glucopyranosyl)oxy)-lup-20(29)-en-28-oic acid methyl ester;
3xcex2-28-hydroxylup-20(29)-en-3-yl-4-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-3-hydroxylup-20(29)-en-28-yl-4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-xcex2-D-xylopyranoside;
3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucppyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex1-lup-20(29)-en-28-oic acid 3-(xcex2-D-glucopyranosyloxy)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex1,4-xcex1-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid;
3xcex1-lup-20(29)-en-28-oic acid 3-((O-6-acetyl-xcex2-D-glucopyranosyl)oxy)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex2-28-hydroxylup-20(29)-en-3-yl-O-xcex1-D-glucopyranosyl-(1xe2x86x924)-O-xcex1-D-glucopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x924)-xcex2-D-glucopyranoside;
3xcex1-3-(sulfooxy)lup-20(29)-en-28-oic acid 28-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-xcex2-D-glucopyranosyl ester;
3-(sulfooxy)lup-20(29)-en-28-oic acid 28-(O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-2,3,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x926)-2,3,4-tri-O-acetyl-xcex2-D-glucopyranosyl) ester;
3xcex1-3-(acetyloxy)lup-20(29)-en-28-oic acid O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-2,3,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x926)-2,3,4-tri-O-acetyl-xcex2-D-glucopyranosyl) ester;
28-(acetyloxy)lup-20(29)-en-3-yl-4-O-(2,3,4,6-tetra-O-acetyl-xcex1-D-glucopyranosyl)-xcex2-D-glucopyranoside triacetate;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-4-O-(2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)-xcex2-D-glucopyranoside triacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-4-O-(2,3,4,6-tetra-O-acetyl-xcex1-D-glucopyranosyl)-xcex2-D-glucopyranoside triacetate;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-lup-20(29)-en-3-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-lup-20(29)-en-3-yl-6-deoxy-xcex1-L-mannopyranoside;
3xcex2-3-((6-deoxy-2-O-xcex2-D-glucopyranosyl-xcex1-L-mannopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((6-deoxy-xcex1-L-mannopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-lup-20(29)-en-3-yl-4-O-xcex2-D-xylopyranosyl-xcex2-D-glucopyranoside;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex1-D-glucopyranoside tetraacetate;
3xcex2-3-hydroxylup-20(29)-en-28-yl-xcex2-D-glucopyranoside 2,3,4,6-tetraacetate;
3xcex2-28-((6-O-D-apio-xcex2-D-furanosyl-xcex2-D-glucopyranosyl)oxy)-28-oxolup-20(29)-en-3-yl-4-O-xcex2-D-galactopyranosyl-xcex2-D-glucopyranosiduronic acid;
3xcex2-3-((2-propenyl)oxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-O-allylbetulinic acidxe2x80x9d);
3xcex2-3,28-dimethoxylup-20(29)-ene (xe2x80x9c3,28-di-O-methylbetulinxe2x80x9d);
3xcex2-3,28-dimethoxylupane (xe2x80x9c3,28-di-O-methyldihydrobetulinxe2x80x9d);
3xcex2-28-methoxylupan-3-ol (xe2x80x9c28-methyldihydrobetulinxe2x80x9d);
3xcex2-3-methoxylup-20(29)-en-28-oic acid (xe2x80x9c3-O-methylbetulinic acidxe2x80x9d);
3xcex2-3-methoxylup-20(29)-en-28-oic acid methyl ester (xe2x80x9cmethyl 3-O-methylbetulinatexe2x80x9d);
8"xgr"-2,6-anhydro-9-O-((3xcex2,18xcex2)-17-carboxy-28-norlupan-3-yl)-1,7,8-trideoxy-8-methyl-3,4,5-tris-O-(phenylmethyl)-L-glycero-D-galactononitol;
2,6-anhydro-9-O-((3xcex2,18xcex2)-17-carboxy-28-norlup-20(29)-en-3-yl)-1,7,8-trideoxy-8-methylene-3,4,5-tris-O-(phenylmethyl)-L-glycero-D-galactononitol;
3xcex1-3-methoxylup-20(29)-en-28-oic acid; or
3xcex1-3-methoxylup-20(29)-en-28-oic acid methyl ester.
Preferably, the compound of formula I is:
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex2-D-glucopyranoside (xe2x80x9c28-acetyl-3-xcex2-D-glucosylbetulinxe2x80x9d);
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex2-D-galactopyranoside (xe2x80x9c28-acetyl-3-xcex2-D-galactosylbetulinxe2x80x9d); or
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-xcex2-D-glucopyranoside (xe2x80x9c3-acetyl-28-xcex2-D-glucosylbetulinxe2x80x9d).
The present invention further provides compositions, useful for the treatment of neuroectodermal tumors comprising a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof, with the proviso that the compound of formula (I) is not:
3xcex2-3-hydroxylup-20(29)-en-28-oic acid (xe2x80x9cbetulinic acidxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol (xe2x80x9cbetulinxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol diacetate (xe2x80x9c3,28-diacetylbetulinxe2x80x9d);
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-acetylbetulinic acidxe2x80x9d);
3xcex2-3-(1-oxobutoxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-butyrylbetulinic acidxe2x80x9d);
3xcex2-3-(2,3-dihydroxycinnamoyl)lup-20(29)-en-28-oic acid (xe2x80x9c3-(2,3-dihydroxycinnamoyl)betulinic acidxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol 3-acetate (xe2x80x9c3-acetylbetulinxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol 28-acetate (xe2x80x9c28-acetylbetulinxe2x80x9d);
3xcex2-3-hydroxylup-20(29)-en-28-oic acid methyl ester (xe2x80x9cmethyl betulinatexe2x80x9d);
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid methyl ester (xe2x80x9cmethyl 3-acetylbetulinatexe2x80x9d);
3xcex2-3-hydroxylup-20(29)-en-28-oic acid ethyl ester (xe2x80x9cethyl betulinatexe2x80x9d);
3xcex2-3-hydroxylup-20(29)-en-28-oic acid butyl ester (xe2x80x9cbutyl betulinatexe2x80x9d);
3xcex2-lupane-3,28-diol (xe2x80x9cdihydrobetulinxe2x80x9d);
3xcex2-3-hydroxylupan-28-oic acid (xe2x80x9cdihydrobetulinic acidxe2x80x9d);
3xcex2-3-hydroxylupan-28-oic acid methyl ester (xe2x80x9cmethyl dihydrobetulinatexe2x80x9d);
3xcex2-3-(acetyloxy)lupan-28-oic acid methyl ester (xe2x80x9cmethyl 3-acetyldihydrobetulinatexe2x80x9d);
3xcex2-3-(acetyloxy)-lupan-28-oic acid (xe2x80x9c3-acetyldihydrobetulinic acidxe2x80x9d);
3xcex2-lupane-3,28-diol diacetate (xe2x80x9c3,28-diacetyldihydrobetulinxe2x80x9d);
3xcex2-lupane-3,28-diol dibutanoate (xe2x80x9c3,28-dibutyryldihydrobetulinxe2x80x9d);
3xcex2-3-(3-methyl-1-oxobutoxy)lupan-28-oic acid (xe2x80x9c3-(3-methylbutryryl)dihydrobetulinic acidxe2x80x9d);
3xcex2-3-((1-oxo-2-butenyl)oxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-(trans-2-butenyl)betulinic acidxe2x80x9d);
3xcex2-3-(2,2-dimethyl-1-oxopropoxy)lupan-28-oic acid (xe2x80x9c3-(2,2-dimethylpropionyl)dihydrobetulinic acidxe2x80x9d);
3xcex1-28-hydroxylup-20(29)-en-3-yl-6-O-(6-deoxy-xcex1-L-mannopyranosyl)-xcex2-D-glucopyranoside;
3xcex1-28-hydroxylup-20(29)-en-3-yl-xcex2-D-glucopyranoside;
3xcex1,4xcex1-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid;
3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid;
3xcex2-28-hydroxylup-20(29)-en-3-yl-xcex2-D-glucopyranoside;
3xcex2-3-hydroxylup-20(29)-en-28-yl-xcex2-D-glucopyranoside;
3xcex2-28(acetyloxy)lup-20(29)-en-3-yl-2-deoxy-xcex1-D-arabinohexopyranoside triacetate;
3xcex2-28(acetyloxy)lup-20(29)-en-3-yl-2-deoxy-xcex2-L-arabinohexopyranoside triacetate;
3xcex2-28(acetyloxy)lup-20(29)-en-3-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside diacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-2-deoxy-xcex1-D-arabinohexopyranoside triacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside diacetate;
3xcex2-28-hydroxylup-20(29)-en-3-yl-2-deoxy-xcex1-D-arabinohexopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-2-deoxy-xcex2-L-arabinohexopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside;
3xcex2-3-hydroxylup-20(29)-en-28-yl-2-deoxy-xcex1-D-arabinohexopyranoside;
3xcex2-lup-20(29)-en-3,28-diyl-bis-xcex2-D-glucopyranoside;
3xcex2-lup-20(29)-en-3,28-diyl-bis-4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-lup-20(29)-en-3,28-diyl-bis-(4-O-(2,3,4,6-tetra-O-acetyl-xcex1-D-glucopyranosyl)-xcex2-D-glucopyranoside hexaacetate;
3xcex2-3-((4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((6-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-hydroxylup-20(29)-en-28-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside;
3xcex2-3-((2-O-xcex1-L-arabinopyranosyl-6-deoxy-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((2-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid xcex2-D-galactopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid 4-O-xcex2-D-galactopyranosyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid methyl ester;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lupan-28-oic acid methyl ester;
3xcex2-3-(acetyloxy)lupan-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex1-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-(acetyloxy)lupan-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid xcex2-D-xylopyranosyl ester;
3xcex2-hydroxylup-20(29)-en-28-oic acid xcex2-D-glucopyranosyl ester 2xe2x80x2,3xe2x80x2,4xe2x80x2,6xe2x80x2-tetrabenzoate;
3xcex2-lup-20(29)-en-28-oic acid (xcex2-D-glucopyranosyloxy)-xcex2-D-glucopyranosyl ester octabenzoate;
3xcex2-lup-20(29)-en-28-oic acid (xcex1-L-arabinopyranosyloxy)-xcex1-L-arabinopyranosyl ester;
3xcex2-lup-20(29)-en-28-oic acid (xcex1-L-arabinopyranosyloxy)-xcex1-L-arabinopyranosyl ester hexabenzoate;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid methyl ester;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lupan-28-oic acid methyl ester;
3xcex2-3-hydroxylupan-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-3-O-xcex2-D-xylopyranosyl-xcex2-D-glucopyranosiduronic acid;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-2-O-xcex2-D-xylopyranosyl-xcex2-D-glucopyranosiduronic acid;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid 6-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranosyl ester;
3xcex1-3-hydroxylup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex1-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex2-28-methoxy-28-oxolup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid methyl ester diacetate;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-xcex2-D-xylopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid diacetate;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4-di-O-acetyl-xcex2-D-xylopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid diacetate;
3xcex2-28-methoxy-28-oxolup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid methyl ester diacetate;
3xcex2-28-methoxy-28-oxolup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4-di-O-acetyl-xcex2-D-xylopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid methyl ester diacetate;
3xcex2-3-((O-xcex1-L-arabinofuranosyl-(1xe2x86x922)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-xcex2-D-glucopyranosyl)oxy)-lup-20(29)-en-28-oic acid;
3xcex2-3-((O-xcex1-L-arabinofuranosyl-(1xe2x86x922)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-xcex2-D-glucopyranosyl)oxy)-lup-20(29)-en-28-oic acid methyl ester;
3xcex2-28-hydroxylup-20(29)-en-3-yl-4-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-3-hydroxylup-20(29)-en-28-yl-4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-xcex2-D-xylopyranoside;
3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex1-lup-20(29)-en-28-oic acid 3-(xcex2-D-glucopyranosyloxy)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex1,4xcex1-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid;
3xcex1-lup-20(29)-en-28-oic acid 3-((O-6-acetyl-xcex2-D-glucopyranosyl)oxy)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex2-28-hydroxylup-20(29)-en-3-yl-O-xcex1-D-glucopyranosyl-(1xe2x86x924)-O-xcex1-D-glucopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x924)-xcex2-D-glucopyranoside;
3xcex1-3-(sulfooxy)lup-20(29)-en-28-oic acid 28-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-xcex2-D-glucopyranosyl ester;
3-(sulfooxy)lup-20(29)-en-28-oic acid 28-(O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-2,3,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x926)-2,3,4-tri-O-acetyl-xcex2-D-glucopyranosyl) ester;
3xcex1-3-(acetyloxy)lup-20(29)-en-28-oic acid O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-2,3,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x926)-2,3,4-tri-O-acetyl-xcex2-D-glucopyranosyl) ester;
28-(acetyloxy)lup-20(29)-en-3-yl-4-O-(2,3,4,6-tetra-O-acetyl-xcex1-D-glucopyranosyl)-xcex2-D-glucopyranoside triacetate;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-4-O-(2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)-xcex2-D-glucopyranoside triacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-4-O-(2,3,4,6-tetra-O-acetyl-xcex1-D-glucopyranosyl)-xcex2-D-glucopyranoside triacetate;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-lup-20(29)-en-3-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-lup-20(29)-en-3-yl-6-deoxy-xcex1-L-mannopyranoside;
3xcex2-3-((6-deoxy-2-O-xcex2-D-glucopyranosyl-xcex1-L-mannopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((6-deoxy-xcex1-L-mannopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-lup-20(29)-en-3-yl-4-O-xcex2-D-xylopyranosyl-xcex2-D-glucopyranoside;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex1-D-glucopyranoside tetraacetate;
3xcex2-3-hydroxylup-20(29)-en-28-yl-xcex2-D-glucopyranoside 2,3,4,6-tetraacetate;
3xcex2-28-((6-O-D-apio-xcex2-D-furanosyl-xcex2-D-glucopyranosyl)oxy)-28-oxolup-20(29)-en-3-yl-4-O-xcex2-D-galactopyranosyl-xcex2-D-glucopyranosiduronic acid;
3xcex2-3-((2-propenyl)oxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-O-allylbetulinic acidxe2x80x9d);
3xcex2-3,28-dimethoxylup-20(29)-ene (xe2x80x9c3,28-di-O-methylbetulinxe2x80x9d);
3xcex2-3,28-dimethoxylupane (xe2x80x9c3,28-di-O-methyldihydrobetulinxe2x80x9d);
3xcex2-28-methoxylupan-3-ol (xe2x80x9c28-methyldihydrobetulinxe2x80x9d);
3xcex2-3-methoxylup-20(29)-en-28-oic acid (xe2x80x9c3-O-methylbetulinic acidxe2x80x9d);
3xcex2-3-methoxylup-20(29)-en-28-oic acid methyl ester (xe2x80x9cmethyl 3-O-methylbetulinatexe2x80x9d);
8"xgr"-2,6-anhydro-9-O-((3xcex2,18xcex2)-17-carboxy-28-norlupan-3-yl)-1,7,8-trideoxy-8-methyl-3,4,5-tris-O-(phenylmethyl)-L-glycero-D-galactononitol;
2,6-anhydro-9-O-((3xcex2,18xcex2)-17-carboxy-28-norlup-20(29)-en-3-yl)-1,7,8-trideoxy-8-methylene-3,4,5-tris-O-(phenylmethyl)-L-glycero-D-galactononitol;
3xcex1-3-methoxylup-20(29)-en-28-oic acid; or
3xcex1-3-methoxylup-20(29)-en-28-oic acid methyl ester.
Preferably, the compositions of the present invention comprise a compound of formula (I) selected from the group consisting of:
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex2-D-glucopyranoside (xe2x80x9c28-acetyl-3-xcex2-D-glucosylbetulinxe2x80x9d);
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex2-D-galactopyranoside (xe2x80x9c28-acetyl-3-xcex2-D-galactosylbetulinxe2x80x9d); and
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-xcex2-D-glucopyranoside (xe2x80x9c3-acetyl-28-xcex2-D-glucosylbetulinxe2x80x9d);
a D-enantiomer, L-enantiomer or racemate thereof,
or a pharmaceutically acceptable salt thereof.
Such compositions can also comprise a pharmaceutically acceptable carrier or vehicle.
The invention further provides methods for the treatment of neuroectodermal tumors, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I): 
wherein
R1 is selected from the group consisting of hydrogen, xe2x80x94SO3H, xe2x80x94PO3H2, xe2x80x94C1-C20 straight or branched chain alkyl, xe2x80x94C2-C20 straight or branched chain alkenyl, xe2x80x94C2-C20 straight or branched chain alkynyl, xe2x80x94(CH2CH2O)nH, xe2x80x94(CH2CH2O)nCH3, xe2x80x94(CH2CH2O)nCH2CH3, xe2x80x94C(O)C6H5, xe2x80x94C(O)C1-C20 straight or branched chain alkyl, xe2x80x94C(O)C2-C20 straight or branched chain alkenyl, xe2x80x94C(O)C2-C20 straight or branched chain alkynyl, myo-inosityl, scyllo-inosityl, a cyclitol, conduritol A, quebrachitol, a monosaccharide, a disaccharide and an oligosaccharide; the xe2x80x94(CH2CH2O)nH, myo-inosityl, scyllo-inosityl, cyclitol, conduritol A, quebrachitol, monosaccharide, disaccharide and oligosaccharide being optionally substituted with one or more xe2x80x94C(O)C1-C20 straight or branched chain alkyl, xe2x80x94C(O)C2-C20 straight or branched chain alkenyl, xe2x80x94C(O)C2-C20 straight or branched chain alkynyl, sulfate, or mono-, di- or tri-phosphate groups;
R2 is selected from the group consisting of xe2x80x94CO2H, xe2x80x94CO2(C6H5), xe2x80x94CO2(C1-C20 straight or branched chain alkyl), xe2x80x94CO2(C2-C20 straight or branched chain alkenyl), xe2x80x94CO2(C2-C20 straight or branched chain alkynyl), xe2x80x94CO2(myo-inosityl), xe2x80x94CO2(scyllo-inosityl), xe2x80x94CO2(cyclitol), xe2x80x94CO2(conduritol A), xe2x80x94CO2(quebrachitol), xe2x80x94CO2(monosaccharide), xe2x80x94CO2(disaccharide), xe2x80x94CO2(oligosaccharide), xe2x80x94CO(OCH2CH2)nOH, xe2x80x94CO(OCH2CH2)nOCH3, xe2x80x94CO(OCH2CH2)nOCH2CH3, xe2x80x94CH2OH, xe2x80x94CH2OSO3H, xe2x80x94CH2OPO3H2, xe2x80x94CH2O(C6H5), xe2x80x94CH2O(C1-C20 straight or branched chain alkyl), xe2x80x94CH2O(C2-C20 straight or branched chain alkenyl), xe2x80x94CH2O(C2-C20 straight or branched chain alkynyl), xe2x80x94CH2O2C(C1-C20 straight or branched chain alkyl), xe2x80x94CH2O2C(C2-C20 straight or branched chain alkenyl), xe2x80x94CH2O2C(C2-C20 straight or branched chain alkynyl), xe2x80x94CH2O(myo-inosityl), xe2x80x94CH2O(scyllo-inosityl), xe2x80x94CH2O(cyclitol), xe2x80x94CH2O(conduritol A), xe2x80x94CH2O(quebrachitol), xe2x80x94CH2O(monosaccharide), xe2x80x94CH2O(disaccharide), xe2x80x94CH2O(oligosaccharide), xe2x80x94CH2(OCH2CH2)nOH, xe2x80x94CH2(OCH2CH2)nOCH3, xe2x80x94CH2(OCH2CH2)nOCH2CH3, xe2x80x94CH2O2C(OCH2CH2)nOH, xe2x80x94CH2O2C(OCH2CH2)nOCH3, and xe2x80x94CH2O2C(OCH2CH2)nOCH2CH3; the myo-inosityl, scyllo-inosityl, cyclitol, conduritol A, quebrachitol, monosaccharide, disaccharide, oligosaccharide, xe2x80x94CH2(OCH2CH2)nOH and xe2x80x94CH2O2C(OCH2CH2)nOH being optionally substituted with one or more xe2x80x94C(O)C1-C20 straight or branched chain alkyl, xe2x80x94C(O)C2-C20 straight or branched chain alkenyl, xe2x80x94C(O)C2-C20 straight or branched chain alkynyl, sulfate, or mono-, di- or tri-phosphate groups;
R2 is selected from the group consisting of xe2x80x94CO2H, xe2x80x94CO2(C6H5), xe2x80x94CO2(C1-C20 straight or branched chain alkyl), xe2x80x94CO2(C2-C20 straight or branched chain alkenyl), xe2x80x94CO2(C2-C20 straight or branced chain alkynyl), xe2x80x94CO2(myo-inosityl), xe2x80x94CO2(scyllo-inosityl), xe2x80x94CO2(cyclitol), xe2x80x94CO2(conduritol A), xe2x80x94CO2(quebrachitol), xe2x80x94CO2(monosaccharide), xe2x80x94CO2(disaccharide), xe2x80x94CO2(oligosaccharide), xe2x80x94CO(OCH2CH2)nOH, xe2x80x94CO(OCH2CH2)nOCH3, xe2x80x94CO(OCH2CH2)nOCH2CH3, xe2x80x94CH2OH, xe2x80x94CH2OSO3H, xe2x80x94CH2OPO3H2, xe2x80x94CH2O(C6H5), xe2x80x94CH2O(C1-C20 straight or branched chain alkyl), xe2x80x94CH2O(C2-C20 straight or branched chain alkenyl), xe2x80x94CH2O(C2-C20 straight or branched chain alkynyl), xe2x80x94CH2O2C(C1-C20 straight or branched chain alkyl), xe2x80x94OH2O2C(C2-C20 straight or branched chain alkenyl), xe2x80x94CH2O2C(C2-C20 straight or branched chain alkynyl), xe2x80x94CH2O(myo-inosityl), xe2x80x94CH2O(scyllo-inosityl), xe2x80x94CH2O(cyclitol), xe2x80x94CH2O(conduritol A), xe2x80x94CH2O(quebrachitol), xe2x80x94CH2O(monosaccharide), xe2x80x94CH2O(disaccharide), xe2x80x94CH2O(oligosaccharide), xe2x80x94CH2(OCH2CH2)nOH, xe2x80x94CH2(OCH2CH2)nOCH3, xe2x80x94CH2(OCH2CH2)nOCH2CH3, xe2x80x94CH2O2C(OCH2CH2)nOH, xe2x80x94CH2O2C(OCH2CH2)nOCH3, and xe2x80x94CH2O2C(OCH2CH2)nOCH2CH3; the myo-inosityl, scyllo-inosityl, cyclitol, conduritol A, quebrachitol, monosaccharide, disaccharide, oligosaccharide, xe2x80x94CH2(OCH2CH2)nOH and xe2x80x94CH2O2C(OCH2CH2)nOH being optionally substituted with one or more =13 C(O)C1-C20 straight or branched chain alkyl, xe2x80x94C(O)C2-C20 straight or branched chain alkenyl, xe2x80x94C(O)C2-C20 straight or branched chain alkynyl, sulfate, or mono-, di- or tri-phosphate groups;
R3 is selected from the group consisting of xe2x80x94C(CH3)(xe2x95x90CH2) and xe2x80x94CH(CH3)2;
each n is independently an integer from 1 to 20;
a D-enantiomer, L-enantiomer, or racemate thereof;
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the present methods comprise administering to a patient a compound of formula (I) selected from the group consisting of:
3xcex2-3-hydroxylup-20(29)-en-28-oic acid (xe2x80x9cbetulinic acidxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol (xe2x80x9cbetulinxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol diacetate (xe2x80x9c3,28-diacetylbetulinxe2x80x9d);
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-acetylbetulinic acidxe2x80x9d);
3xcex2-3-(1-oxobutoxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-butyrylbetulinic acidxe2x80x9d);
3xcex2-3-(2,3-dihydroxycinnamoyl)lup-20(29)-en-28-oic acid (xe2x80x9c3-(2,3-dihydroxycinnamoyl)betulinic acidxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol 3-acetate (xe2x80x9c3-acetylbetulinxe2x80x9d);
3xcex2-lup-20(29)-ene-3,28-diol 28-acetate (xe2x80x9c28-acetylbetulinxe2x80x9d);
3xcex2-3-hydroxylup-20(29)-en-28-oic acid methyl ester (xe2x80x9cmethyl betulinatexe2x80x9d);
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid methyl ester (xe2x80x9cmethyl 3-acetylbetulinatexe2x80x9d);
3xcex2-3-hydroxylup-20(29)-en-28-oic acid ethyl ester (xe2x80x9cethyl betulinatexe2x80x9d);
3xcex2-3-hydroxylup-20(29)-en-28-oic acid butyl ester (xe2x80x9cbutyl betulinatexe2x80x9d);
3xcex2-lupane-3,28-diol (xe2x80x9cdihydrobetulinxe2x80x9d);
3xcex2-3-hydroxylupan-28-oic acid (xe2x80x9cdihydrobetulinic acidxe2x80x9d);
3xcex2-3-hydroxylupan-28-oic acid methyl ester (xe2x80x9cmethyl dihydrobetulinatexe2x80x9d);
3xcex2-3-(acetyloxy)lupan-28-oic acid methyl ester (xe2x80x9cmethyl 3-acetyldihydrobetulinatexe2x80x9d);
3xcex2-3-(acetyloxy)-lupan-28-oic acid (xe2x80x9c3-acetyldihydrobetulinic acidxe2x80x9d);
3xcex2-lupane-3,28-diol diacetate (xe2x80x9c3,28-diacetyldihydrobetulinxe2x80x9d);
3xcex2-lupane-3,28-diol dibutanoate (xe2x80x9c3,28-dibutyryldihydrobetulinxe2x80x9d);
3xcex2-3-(3-methyl-1-oxobutoxy)lupan-28-oic acid (xe2x80x9c3-(3-methylbutryryl)dihydrobetulinic acidxe2x80x9d);
3xcex2-3-((1-oxo-2-butenyl)oxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-(trans-2-butenyl)betulinic acidxe2x80x9d);
3xcex2-3-(2,2-dimethyl-1-oxopropoxy)lupan-28-oic acid (xe2x80x9c3-(2,2-dimethylpropionyl)dihydrobetulinic acidxe2x80x9d);
3xcex1-28-hydroxylup-20(29)-en-3-yl-6-O-(6-deoxy-xcex1-L-mannopyranosyl)-xcex2-D-glucopyranoside;
3xcex1-28-hydroxylup-20(29)-en-3-yl-xcex2-D-glucopyranoside;
3xcex1,4xcex1-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid;
3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid;
3xcex2-28-hydroxylup-20(29)-en-3-yl-xcex2-D-glucopyranoside;
3xcex2-3-hydroxylup-20(29)-en-28-yl-xcex2-D-glucopyranoside;
3xcex2-28(acetyloxy)lup-20(29)-en-3-yl-2-deoxy-xcex1-D-arabinohexopyranoside triacetate;
3xcex2-28(acetyloxy)lup-20(29)-en-3-yl-2-deoxy-xcex2-L-arabinohexopyranoside triacetate;
3xcex2-28(acetyloxy)lup-20(29)-en-3-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside diacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-2-deoxy-xcex1-D-arabinohexopyranoside triacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside diacetate;
3xcex2-28-hydroxylup-20(29)-en-3-yl-2-deoxy-xcex1-D-arabinohexopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-2-deoxy-xcex2-L-arabinohexopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside;
3xcex2-3-hydroxylup-20(29)-en-28-yl-2-deoxy-xcex1-D-arabinohexopyranoside;
3xcex2-lup-20(29)-en-3,28-diyl-bis-xcex2-D-glucopyranoside;
3xcex2-lup-20(29)-en-3,28-diyl-bis-4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-lup-20(29)-en-3,28-diyl-bis-(4-O-(2,3,4,6-tetra-O-acetyl-xcex1-D-glucopyranosyl)-xcex2-D-glucopyranoside hexaacetate;
3xcex2-3-((4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((6-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-hydroxylup-20(29)-en-28-yl-2,6-dideoxy-xcex2-L-arabinohexopyranoside;
3xcex2-3-((2-O-xcex1-L-arabinopyranosyl-6-deoxy-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((2-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid xcex2-D-galactopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid 4-O-xcex2-D-galactopyranosyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid methyl ester;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-oic acid xcex2-D-glucopyranosyl ester,
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid 3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lupan-28-oic acid methyl ester;
3xcex2-3-(acetyloxy)lupan-28-oic acid 2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl ester;
3xcex1-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-(acetyloxy)lupan-28-oic acid xcex2-D-glucopyranosyl ester,
3xcex2-3-hydroxylup-20(29)-en-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-3-hydroxylup-20(29)-en-28-oic acid xcex2-D-xylopyranosyl ester;
3xcex2-hydroxylup-20(29)-en-28-oic acid xcex2-D-glucopyranosyl ester 2xe2x80x2,3xe2x80x2,4xe2x80x2,6xe2x80x2-tetrabenzoate;
3xcex2-lup-20(29)-en-28-oic acid (xcex2-D-glucopyranosyloxy)-xcex2-D-glucopyranosyl ester octabenzoate;
3xcex2-lup-20(29)-en-28-oic acid (xcex1-L-arabinopyranosyloxy)-xcex1-L-arabinopyranosyl ester;
3xcex2-lup-20(29)-en-28-oic acid (xcex1-L-arabinopyranosyloxy)-xcex1-L-arabinopyranosyl ester hexabenzoate;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid methyl ester;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lupan-28-oic acid methyl ester;
3xcex2-3-hydroxylupan-28-oic acid xcex2-D-glucopyranosyl ester;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-3-O-xcex2-D-xylopyranosyl-xcex2-D-glucopyranosiduronic acid;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-2-O-xcex2-D-xylopyranosyl-xcex2-D-glucopyranosiduronic acid;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid 6-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranosyl ester;
3xcex1-3-hydroxylup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex1-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex2-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex2-28-methoxy-28-oxolup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid methyl ester diacetate;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-xcex2-D-xylopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid diacetate;
3xcex2-17-carboxy-28-norlup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4-di-O-acetyl-xcex2-D-xylopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid diacetate;
3xcex2-28-methoxy-28-oxolup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid methyl ester diacetate;
3xcex2-28-methoxy-28-oxolup-20(29)-en-3-yl-O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x922)-O-3,4-di-O-acetyl-xcex2-D-xylopyranosyl-(1xe2x86x922)-xcex2-D-glucopyranosiduronic acid methyl ester diacetate;
3xcex2-3-((O-xcex1-L-arabinofuranosyl-(1xe2x86x922)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-xcex2-D-glucopyranosyl)oxy)-lup-20(29)-en-28-oic acid;
3xcex2-3-((O-xcex1-L-arabinofuranosyl-(1xe2x86x922)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-xcex2-D-glucopyranosyl)oxy)-lup-20(29)-en-28-oic acid methyl ester;
3xcex2-28-hydroxylup-20(29)-en-3-yl-4-O-xcex2-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-3-hydroxylup-20(29)-en-28-yl-4-O-xcex1-D-glucopyranosyl-xcex2-D-glucopyranoside;
3xcex2-28-hydroxylup-20(29)-en-3-yl-xcex2-D-xylopyranoside;
3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1 6)-O-xcex2-D-glucopyranosyl ester;
3xcex1-lup-20(29)-en-28-oic acid 3-(xcex2-D-glucopyranosyloxy)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex1,4-xcex1-3-(xcex2-D-glucopyranosyloxy)lup-20(29)-en-28-oic acid;
3xcex1-lup-20(29)-en-28-oic acid 3-((O-6-acetyl-xcex2-D-glucopyranosyl)oxy)-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-O-xcex2-D-glucopyranosyl ester;
3xcex2-28-hydroxylup-20(29)-en-3-yl-O-xcex1-D-glucopyranosyl-(1xe2x86x924)-O-xcex1-D-glucopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x924)-xcex2-D-glucopyranoside;
3xcex1-3-(sulfooxy)lup-20(29)-en-28-oic acid 28-O-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-xcex2-D-glucopyranosyl-(1xe2x86x926)-xcex2-D-glucopyranosyl ester;
3-(sulfooxy)lup-20(29)-en-28-oic acid 28-(O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-2,3,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x926)-2,3,4-tri-O-acetyl-xcex2-D-glucopyranosyl) ester;
3xcex1-3-(acetyloxy)lup-20(29)-en-28-oic acid O-2,3,4-tri-O-acetyl-6-deoxy-xcex1-L-mannopyranosyl-(1xe2x86x924)-O-2,3,6-tri-O-acetyl-xcex2-D-glucopyranosyl-(1xe2x86x926)-2,3,4-tri-O-acetyl-xcex2-D-glucopyranosyl) ester;
28-(acetyloxy)lup-20(29)-en-3-yl-4-O-(2,3,4,6-tetra-O-acetyl-xcex1-D-glucopyranosyl)-xcex2-D-glucopyranoside triacetate;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-4-O-(2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)xcex2-D-glucopyranoside triacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-4-O-(2,3,4,6-tetra-O-acetyl-xcex1-D-glucopyranosyl)-xcex2-D-glucopyranoside triacetate;
3xcex2-3-((2,3,4,6-tetra-O-acetyl-xcex2-D-glucopyranosyl)oxy)lup-20(29)-en-28-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-lup-20(29)-en-3-yl-xcex2-D-glucopyranoside tetraacetate;
3xcex2-lup-20(29)-en-3-yl-6-deoxy-xcex1-L-mannopyranoside;
3xcex2-3-((6-deoxy-2-O-xcex2-D-glucopyranosyl-xcex1-L-mannopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-3-((6-deoxy-xcex1-L-mannopyranosyl)oxy)lup-20(29)-en-28-oic acid;
3xcex2-lup-20(29)-en-3-yl-4-O-xcex2-D-xylopyranosyl-xcex2-D-glucopyranoside;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex1-D-glucopyranoside tetraacetate;
3xcex2-3-hydroxylup-20(29)-en-28-yl-xcex2-D-glucopyranoside 2,3,4,6-tetraacetate;
3xcex2-28-((6-O-D-apio-xcex2-D-furanosyl-xcex2-D-glucopyranosyl)oxy)-28-oxolup-20(29)-en-3-yl-4-O-xcex2-D-galactopyranosyl-xcex2-D-glucopyranosiduronic acid;
3xcex2-3-((2-propenyl)oxy)lup-20(29)-en-28-oic acid (xe2x80x9c3-O-allylbetulinic acidxe2x80x9d);
3xcex2-3,28-dimethoxylup-20(29)-ene (xe2x80x9c3,28-di-O-methylbetulinxe2x80x9d);
3xcex2-3,28-dimethoxylupane (xe2x80x9c3,28-di-O-methyldihydrobetulinxe2x80x9d);
3xcex2-28-methoxylupan-3-ol (xe2x80x9c28-methyldihydrobetulinxe2x80x9d);
3xcex2-3-methoxylup-20(29)-en-28-oic acid (xe2x80x9c3-O-methylbetulinic acidxe2x80x9d);
3xcex2-3-methoxylup-20(29)-en-28-oic acid methyl ester (xe2x80x9cmethyl 3-O-methylbetulinatexe2x80x9d);
9"xgr"-2,6-anhydro-9-O-((3xcex2,18xcex2)-17-carboxy-28-norlupan-3-yl)-1,7,8-trideoxy-8-methyl-3,4,5-tris-O-(phenylmethyl)-L-glycero-D-galactononitol;
2,6-anhydro-9-O-((3xcex2,18xcex2)-17-carboxy-28-norlup-20(29)-en-3-yl)-1,7,8-trideoxy-8-methylene-3,4,5-tris-O-(phenylmethyl)-L-glycero-D-galactononitol;
3xcex1-3-methoxylup-20(29)-en-28-oic acid;
3xcex1-3-methoxylup-20(29)-en-28-oic acid methyl ester;
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex2-D-glucopyranoside (xe2x80x9c28-acetyl-3-xcex2-D-glucosylbetulinxe2x80x9d);
3xcex2-28-(acetyloxy)lup-20(29)-en-3-yl-xcex2-D-galactopyranoside (xe2x80x9c28-acetyl-3-xcex2-D-galactosylbetulinxe2x80x9d); and
3xcex2-3-(acetyloxy)lup-20(29)-en-28-yl-xcex2-D-glucopyranoside (xe2x80x9c3-acetyl-28-xcex2-D-glucosylbetulinxe2x80x9d);
a D-enantiomer, L-enantiomer or racemate thereof,
or a pharmaceutically acceptable salt thereof.
In one embodiment of the invention, the compound of formula (I) is administered within a composition comprising a pharmaceutically acceptable carrier or vehicle.
The compounds of formula (I) may be administered by a variety of methods including orally, sublingually, intranasally, intramuscularly, intravenously, subcutaneously, intravaginally, transdermally, rectally, by inhalation, or as a mouthwash.
The compositions of the invention and the methods disclosed herein are particularly advantageous for the treatment of neuroectodermal tumors that are resistant to most commonly used chemotherapeutic agents. In one embodiment, the method involves administering betulinic acid and derivatives thereof and/or compositions comprising the same to a subject systemically. In another embodiment, the method involves the application, of betulinic acid or its derivatives to a tumor locally. In some preferred embodiment, betulinic acid is systemically administered to a patient inflict with a doxorubin-resistant neuroectodermal tumor.